The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages

The CDK inhibitor, R‐roscovitine, promotes eosinophil apoptosis by down‐regulation of Mcl‐1

“…Mcl-1 is now generally accepted to be the pre-eminent Bcl-2 homologue responsible for neutrophil survival and evidence is increasing for a central role in eosinophil survival. This evidence includes the granulopenic phenotype of the Mcl 1 À/À mouse [48] and the finding that dexamethasone (a prototype corticosteroid) driven eosinophil apoptosis is associated with down-regulation of Mcl-1 at the protein level [39]. These pro-survival Bcl-2 homologues are short-lived compared to their pro-apoptotic counterparts, a feature which presumably biases granulocyte cells towards early, constitutive apoptosis.…”

“…This drug has been used over a concentration range of 10-300 lM in the literature and often at 100 lM in granulocyte work [47,48]. At 300 lM in combination with TNF accelerated apoptosis has been observed [49].…”

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

“…The following mice have been described previously: mice carrying a bcl-x gene with 2 loxP sequencers at the promoter region and a second intron (bcl-x flox/flox ), 15 a mcl-1 gene encoding amino acids 1 through 179 flanked by 2 loxP sequencers (mcl-1 flox/flox ) 4 and heterozygous pf4-Cre transgenic mice expressing Cre recombinase gene under regulation of the promoter of the platelet factor 4 gene. 30 Megakaryocytic lineage-specific Bcl-xL knockout mice (bcl-x flox/flox pf4-Cre) have been also described previously.…”

“…2 Mx1-Cre-inducible deletion of the mcl-1 gene has been reported to cause rapid, fatal, multi-lineage hematopoietic failure of HSCs (hematopoietic stem cells), CMPs (common myeloid progenitor cells), GMPs (granulocyte monocyte progenitor cells) and CLPs (common lymphoid progenitor cells), 3 thus establishing the concept that Mcl-1 is important for the survival of hematopoietic cells in early differential stages of hematopoiesis. 2 On the other hand, recent studies have revealed that Mcl-1 is required for granulocyte development but not for the development of monocytes and macrophages, 4,5 suggesting a selective role of Mcl-1 in the terminally differentiated stages of hematopoiesis. In addition, loss-of-function studies have demonstrated that Bcl-xL is an essential pro-survival molecule of the definitive erythrocytes, 6 while Bcl-2 and A1 are involved in the survival of lymphocytes and neutrophils, respectively.…”

The Bcl-2 apoptotic switch in cancer development and therapy

“…Bcl-2 is essential for the survival of kidney and melanocyte stem cells, as well as mature B and T lymphoid cells (Nakayama et al, 1993(Nakayama et al, , 1994Veis et al, 1993) and Bcl-x L is needed to sustain erythroid and neuronal cells (Motoyama et al, 1995(Motoyama et al, , 1999Wagner et al, 2000). Remarkably, Mcl-1 is obligatory for the survival and implantation of the zygote (Rinkenberger et al, 2000), and its conditional elimination has revealed critical roles in B and T lymphopoiesis and early hematopoiesis (Opferman et al, 2003(Opferman et al, , 2005, as well as in mature neutrophils but not macrophages (Dzhagalov et al, 2006). The particularly severe defects produced by the loss of Mcl-1 or Bcl-x L may reflect their key roles as guards on Bak (see above) .…”